Neurocognitive Function in Children with Primary Hypertension after Initiation of Antihypertensive Therapy.

OBJECTIVE: To determine the change in neurocognitive test performance in children with primary hypertension after initiation of antihypertensive therapy. STUDY DESIGN: Subjects with hypertension and normotensive control subjects had neurocognitive testing at baseline and again after 1 year, during which time the subjects with hypertension received antihypertensive therapy. Subjects completed tests of general intelligence, attention, memory, executive function, and processing speed, and parents completed rating scales of executive function. RESULTS: Fifty-five subjects with hypertension and 66 normotensive control subjects underwent both baseline and 1-year assessments. Overall, the blood pressure (BP) of subjects with hypertension improved (24-hour systolic BP load: mean baseline vs 1 year, 58% vs 38%, P < .001). Primary multivariable analyses showed that the hypertension group improved in scores of subtests of the Rey Auditory Verbal Learning Test, Grooved Pegboard, and Delis-Kaplan Executive Function System Tower Test (P < .05). However, the control group also improved in the same measures with similar effects sizes. Secondary analyses by effectiveness of antihypertensive therapy showed that subjects with persistent ambulatory hypertension at 1 year (n = 17) did not improve in subtests of Rey Auditory Verbal Learning Test and had limited improvement in Grooved Pegboard. CONCLUSIONS: Overall, children with hypertension did not improve in neurocognitive test performance after 1 year of antihypertensive therapy, beyond that also seen in normotensive controls, suggesting improvements with age or practice effects because of repeated neurocognitive testing. However, the degree to which antihypertensive therapy improves BP may affect its impact upon neurocognitive function.

Neurocognitive Function in Children with Primary Hypertension.

OBJECTIVE: To compare neurocognitive test performance of children with primary hypertension with that of normotensive controls. STUDY DESIGN: Seventy-five children (10-18 years of age) with newly diagnosed, untreated hypertension and 75 frequency-matched normotensive controls had baseline neurocognitive testing as part of a prospective multicenter study of cognition in primary hypertension. Subjects completed tests of general intelligence, attention, memory, executive function, and processing speed. Parents completed rating scales of executive function and the Sleep-Related Breathing Disorder scale of the Pediatric Sleep Questionnaire (PSQ-SRBD). RESULTS: Hypertension and control groups did not differ significantly in age, sex, maternal education, income, race, ethnicity, obesity, anxiety, depression, cholesterol, glucose, insulin, and C-reactive protein. Subjects with hypertension had greater PSQ-SRBD scores (P = .04) and triglycerides (P = .037). Multivariate analyses showed that hypertension was independently associated with worse performance on the Rey Auditory Verbal Learning Test (List A Trial 1, P = .034; List A Total, P = .009; Short delay recall, P = .013), CogState Groton Maze Learning Test delayed recall (P = .002), Grooved Pegboard dominant hand (P = .045), and Wechsler Abbreviated Scales of Intelligence Vocabulary (P = .016). Results indicated a significant interaction between disordered sleep (PSQ-SRBD score) and hypertension on ratings of executive function (P = .04), such that hypertension heightened the association between increased disordered sleep and worse executive function. CONCLUSIONS: Youth with primary hypertension demonstrated significantly lower performance on neurocognitive testing compared with normotensive controls, in particular, on measures of memory, attention, and executive functions.

Recent clinical and translational advances in pediatric hypertension.

Epidemiological reports describe a child population increase in BP level and an increase in prevalence of hypertension, that is largely, but not entirely, driven by a concurrent increase in childhood obesity. Given current estimates, ≈10% of adolescents have hypertension or prehypertension. In addition to obesity, dietary salt intake and waist circumference, a marker of visceral obesity, are found to be independently associated with the rise in BP among children and adolescents. Dietary salt intake in urban children is well above recommended levels largely because of consumption of processed and fast foods. Childhood exposures, such as stress,52 salt, and fructose, as well as lifestyles, including food sources, sleep patterns, and reductions in physical activity may have a role in obesity-high BP associations. In addition, clinical and translational evidence is mounting that intrauterine exposures alter can effect changes in fetal development that have an enduring effect on cardiovascular and metabolic function later in life. These effects can be detected even in children who are products of a term otherwise normal pregnancy. Hypertension in childhood has been defined statistically (BP ≥ 95th percentile) because of lack of outcome data that links a BP level with heightened risk for future cardiovascular events. Therefore, primary hypertension had been considered a risk factor for later hypertension in adulthood. Intermediate markers of TOD, including cardiac hypertrophy, vascular stiffness, and increases in cIMT, are detectable in adolescents with primary hypertension. Evidence that vascular injury is present in the early phase of hypertension and even in prehypertension warrants consideration on the current definition of pediatric hypertension. With further studies on TOD and other risk factors in addition to high BP, it may be possible to shift from a statistical definition to a definition of childhood hypertension that is evidence based. Preventing or reducing childhood obesity would have substantial benefit in countering the documented increase in BP levels and prevalence of high BP in childhood. Weight control in overweight and obese children, along with dietary changes 53 and increases in physical activity,54 has benefit on BP levels in childhood. Prevention of childhood obesity and BP risk will require multiple levels of intervention, including public health, health policy, and attention to food supply to foster the necessary lifestyle changes to prevent and reduce childhood obesity.

Fibroblast growth factor-23 in obese, normotensive adolescents is associated with adverse cardiac structure.

OBJECTIVES: Fibroblast growth factor-23 (FGF23) is a biomarker for cardiovascular disease. Obesity may promote FGF23 production in the absence of chronic kidney disease. We sought to determine among normotensive African American adolescents whether FGF23 levels are greater in obese compared with normal-weight adolescents and to determine the relationship of FGF23 with markers of cardiac structure and insulin resistance. STUDY DESIGN: Cross-sectional data were obtained from a cohort of 130 normotensive, African American adolescents ages 13-18 years without chronic kidney disease; 74 were obese; 56 were normal weight. Plasma C-terminal FGF23, fasting glucose and insulin, and high-sensitivity C-reactive protein were measured; participants underwent M-mode echocardiography. RESULTS: FGF23 was skewed and approximately normally distributed after natural log transformation (logFGF23). FGF23 levels were greater in obese vs normal-weight participants (geometric mean 43 vs 23 RU/mL, P < .01). FGF23 values were significantly greater in participants with eccentric or concentric cardiac hypertrophy compared with those without hypertrophy P < .01). LogFGF23 directly correlated with body mass index, body mass index z-score, waist circumference, fasting insulin levels, and homeostasis model assessment scores. Regression models adjusted for age, sex, and high-sensitivity C-reactive protein suggest that each 10% increase in FGF23 is associated with a 1.31 unit increase in left ventricular mass (P < .01), a 0.29-unit increase in left ventricular mass index (P < .01), and a 0.01-unit increase in left atrial dimension indexed to height (P = .02). CONCLUSIONS: In this sample of obese African American adolescents, FGF23 blood levels were associated with abnormal cardiac structure. We postulate that FGF23 may be an early marker of cardiac injury in obese but otherwise-healthy African American adolescents.

A double-blind randomized trial of fish oil to lower triglycerides and improve cardiometabolic risk in adolescents.

OBJECTIVES: To determine the efficacy of 4 g/day fish oil to lower triglycerides and impact lipoprotein particles, inflammation, insulin resistance, coagulation, and thrombosis. STUDY DESIGN: Participants (n = 42, age 14 ± 2 years) with hypertriglyceridemia and low-density lipoprotein (LDL) cholesterol <160 mg/dL were enrolled in a randomized, double-blind, crossover trial comparing 4 g of fish oil daily with placebo. Treatment interval was 8 weeks with a 4-week washout. Lipid profile, lipoprotein particle distribution and size, glucose, insulin, high-sensitivity C-reactive protein, interleukin-6, fibrinogen, plasminogen activator inhibitor-1, and thrombin generation were measured. RESULTS: Baseline lipid profile was total cholesterol 194 (5.4) mg/dL (mean [SE]), triglycerides 272 (21) mg/dL, high-density lipoprotein cholesterol 39 (1) mg/dL, and LDL cholesterol 112 (3.7) mg/dl. LDL particle number was 1614 (60) nmol/L, LDL size was 19.9 (1.4) nm, and large very low-density lipoprotein/chylomicron particle number was 9.6 (1.4) nmol/L. Triglycerides decreased on fish oil treatment but the difference was not significant compared with placebo (-52 ± 16 mg/dL vs -16 ± 16 mg/dL). Large very low-density lipoprotein particle number was reduced (-5.83 ± 1.29 nmol/L vs -0.96 ± 1.31 nmol/L; P < .0001). There was no change in LDL particle number or size. There was a trend towards a lower prothrombotic state (lower fibrinogen and plasminogen activator inhibitor-1; .10 > P > .05); no other group differences were seen. CONCLUSIONS: In children, fish oil (4 g/day) lowers triglycerides slightly and may have an antithrombotic effect but has no effect on LDL particles.

High risk blood pressure and obesity increase the risk for left ventricular hypertrophy in African-American adolescents.

OBJECTIVE: To examine the relative effects of high blood pressure (HBP) and obesity on left ventricular mass (LVM) among African-American adolescents; and if metabolic or inflammatory factors contribute to LVM. STUDY DESIGN: Using a 2 × 2 design, African-American adolescents were stratified by body mass index percentile (body mass index <95th percentile = non-obese; ≥ 95th percentile = obese) and average blood pressure (BP) (normal BP <120/80 mm Hg; HBP ≥ 120/80). Glucose, insulin, insulin resistance, lipids, and inflammatory cytokines were measured. From echocardiography measures of LVM, calculated LVM index (LVMI) ≥ 95th percentile defined left ventricular hypertrophy (LVH). RESULTS: Data included 301 adolescents (48% female), mean age 16.2 years, 51% obese, and 29% HBP. LVMI was highest among adolescents with both obesity and HBP. The multiplicative interaction of obesity and HBP on LVH was not significant (OR = 2.35, P = .20) but the independent additive associations of obesity and HBP with log-odds of LVH were significant; obesity OR = 3.26, P < .001; HBP OR = 2.92, P < .001. Metabolic and inflammatory risk factors were associated with obesity, but had no independent association with LVMI. Compared with those with average systolic BP (SBP) <75th percentile, adolescents with SBP from the 75th percentile to 90th percentile had higher LVMI (33.2 vs 38.7 g/m(2.7), P < .001) and greater LVH (18% vs 43%, P < .001), independent of obesity. CONCLUSIONS: Prevalence of LVH is highest among African-American adolescents with average BP ≥ 120/80 mm Hg and obesity. There also is an independent association of LVMI with BP, beginning at the 75th SBP percentile.

Parental assessment of executive function and internalizing and externalizing behavior in primary hypertension after anti-hypertensive therapy.

OBJECTIVE: To determine the change in parental ratings of executive function and behavior in children with primary hypertension after anti-hypertensive therapy. STUDY DESIGN: Parents of subjects with untreated hypertension and control subjects completed the Behavior Rating Inventory of Executive Function (BRIEF) to assess behavioral correlates of executive function and the Child Behavior Checklist (CBCL) to assess internalizing and externalizing behaviors. Subjects with hypertension subsequently received anti-hypertensive therapy to achieve casual blood pressure (BP)<95th percentile. After 12 months, all parents again completed the BRIEF and CBCL. RESULTS: Twenty-two subjects with hypertension and 25 normotensive control subjects underwent both baseline and 12-month assessments. The BP of subjects with hypertension improved (24-hour systolic BP [SBP] load: mean baseline versus 12-months, 60% versus 25%, P<.001). Parent ratings of executive function improved from baseline to 12 months in the subjects with hypertension (BRIEF Global Executive Composite T-score, Delta=-5.9, P=0.001), but not in the normotensive control subjects (Delta=-0.36, P=.83). In contrast, T-scores on the CBCL Internalizing and Externalizing summary scales did not change significantly from baseline to 12 months in either subjects with hypertension or control subjects. CONCLUSIONS: Children with hypertension demonstrated improvement in parental ratings of executive function after 12 months of anti-hypertensive therapy.

Parental assessments of internalizing and externalizing behavior and executive function in children with primary hypertension.

OBJECTIVE: To determine the relations between hypertension and parental ratings of behavior and executive functions in children with primary hypertension and to examine the potential moderating influence of obesity. STUDY DESIGN: Hypertensive and normotensive control groups were matched for age, sex, race, intelligence quotient, maternal education, household income, and obesity. Parents completed the Child Behavior Checklist to assess Internalizing and Externalizing problems and the Behavior Rating Inventory of Executive Function to assess behavioral correlates of executive function. RESULTS: Thirty-two hypertensive subjects and 32 normotensive control subjects (aged 10 to 18 years) were enrolled. On the Child Behavior Checklist, hypertensives had higher Internalizing T-scores (53 vs 44.5, P = .02) with 37% falling within the clinically significant range vs 6% of control subjects (P = .005). Internalizing score increased with increasing body mass index percentile in hypertensive but not normotensive subjects. Hypertensives had worse Behavior Rating Inventory of Executive Function Global Executive Composite T-scores compared with control subjects (50 vs 43, P = .009). CONCLUSIONS: Children with both hypertension and obesity demonstrate higher rates of clinically significant internalizing problems, and hypertensives (irrespective of obesity) demonstrate lower parental ratings of executive function compared with normotensive control subjects.

Efficacy and safety of extended release metoprolol succinate in hypertensive children 6 to 16 years of age: a clinical trial experience.

OBJECTIVE: To evaluate the efficacy, tolerability, and blood pressure (BP) lowering effect of extended release metoprolol succinate (ER metoprolol) in children 6 to 16 years of age with established hypertension. STUDY DESIGN: Patients were randomized to one of four treatment arms: placebo or ER metoprolol (0.2 mg/kg, 1.0 mg/kg, or 2.0 mg/kg). Data were analyzed on 140 intent-to-treat patients. RESULTS: Mean age (+/-SD) was 12.5 +/- 2.8 years and mean baseline BP was 132/78 +/- 9/9 mmHg. Following 4 weeks of treatment, mean changes in sitting BP were: placebo = -1.9/-2.1 mmHg; ER metoprolol 0.2 mg/kg = -5.2/-3.1 mmHg; 1.0 mg/kg = -7.7/-4.9 mmHg; 2.0 mg/kg = -6.3/-7.5 mmHg. Compared with placebo, ER metoprolol significantly reduced systolic blood pressure (SBP) at the 1.0 and 2.0 mg/kg dose (P = .027 and P = .049, respectively), reduced diastolic blood pressure (DBP) at the 2.0 mg/kg dose (P = .017), and showed a statistically significant dose response relationship for the placebo-corrected change in DBP from baseline. There were no serious adverse events or adverse events requiring study drug discontinuation among patients receiving active therapy. CONCLUSION: These data indicate that ER metoprolol is an effective and well-tolerated treatment for hypertension in children.

The relationship of body mass index and blood pressure in primary care pediatric patients.

OBJECTIVE: To determine whether an association of overweight, or risk of overweight, and blood pressure can be detected in children in the pediatric primary care practice setting. STUDY DESIGN: We examined electronic medical record (EMR) data from primary care practices on 18,618 children age 2 to 19 years. Each child was classified on the basis of age- and sex-specific body mass index (BMI) percentile as normal weight (BMI < 85th percentile), at risk for overweight (BMI > or = 85th and < 95th percentile), or overweight (BMI > or = 95th percentile). BMI Z-score and height Z-score were computed. Systolic and diastolic blood pressures were compared among age-sex-BMI groups. RESULTS: Among children in primary care pediatric practices, 16.7% were at risk of overweight and 20.2% were overweight. With increasing BMI status there was a significant increase in both systolic blood pressure (P < .001) and diastolic blood pressure (P < .001). The association of higher blood pressure with increasing BMI status was present in all age groups. CONCLUSIONS: Clinical data from pediatric primary care practices verify the high prevalence of childhood overweight. The effect of overweight on blood pressure is present in childhood and can be detected even in children as young as 2 to 5 years.

Evaluation of Hypertension in Older Children and Adolescents.

Hypertension occurs in children as well as adults. Unlike adults, the rates of hypertension in childhood are lower and the methods of diagnosis and evaluation vary somewhat. In the following review on the diagnosis and management of hypertension in older children, three typical cases will be discussed. Key issues in the methods and criteria used in the diagnosis of hypertension will be described. The secondary causes of hypertension in the young, the characteristics of essential hypertension, and the management of hypertension in the young will also be discussed in the context of typical cases. (c)1999 by Le Jacq Communications, Inc.